Antibody semorinemab reduces tau pathology in a transgenic mouse model and engages tau in patients with Alzheimer’s disease

Abstract

Tau has become an attractive alternative target for passive immunotherapy efforts for Alzheimer’s disease (AD). The anatomical distribution and extent of tau pathology correlate with disease course and severity better than other disease markers to date. We describe here the generation, preclinical characterization, and phase 1 clinical characterization of semorinemab, a humanized anti-tau monoclonal antibody with an immunoglobulin G4 (igG4) isotype backbone. Semorinemab binds all six human tau isoforms and protects neurons against tau oligomer neurotoxicity in cocultures of neurons and microglia. In addition, when administered intraperitoneally once weekly for 13 weeks, murine versions of semorinemab reduced the accumulation of tau pathology in a transgenic mouse model of tauopathy, independent of antibody effector function status. Semorinemab also showed clear evidence of target engagement in vivo, with increases in systemic tau concentrations observed in tau transgenic mice, nonhuman primates, and humans. Higher concentrations of systemic tau were observed after dosing in AD participants compared to healthy control participants. No concerning safety signals were observed in the phase 1 clinical trial at single doses up to 16,800 mg and multiple doses totaling 33,600 mg in a month.

Immunotherapies for Neurodegenerative Diseases

“…Preliminary findings from phase I trial indicated that the treatment is tolerable and safe, but was not efficiently immunogenic; therefore, a second-generation vaccine, ACI-35.030, has been generated. ACI-35.030 is 5 times more immunogenic than its predecessor and will replace ACI-35 in the phase I/II safety and tolerability clinical trial ( 183 ).…”

Positron Emission Tomography in Animal Models of Tauopathies

“…Tau has been an important target in therapeutics development for AD and primary tauopathies. Immunotherapies semorinemab, gosuranemab (Boxer et al, 2019;Ayalon et al, 2021;Grossman, 2021;Mullard, 2021;Novak et al, 2021), antisense oligonucleotides (DeVos et al, 2017), and aggregation inhibitors are at different stages of clinical trials (Congdon and Sigurdsson, 2018).…”

“…Transgenic animal models recapitulating human tauopathy have enabled understanding of disease mechanisms and facilitated the development of treatment strategies ( Albert et al, 2019;Roberts et al, 2020;Ayalon et al, 2021). Varieties of transgenic mouse lines with mutations on MAPT gene including P301S (PS19), P301L (JNPL3, rTg4510, pR5) ( Lewis et al, 2000;Ramsden et al, 2005;Santacruz et al, 2005;Yoshiyama et al, 2007;de Calignon et al, 2012), knock-out hTau (Andorfer et al, 2003), and knockin (Hashimoto et al, 2019;Saito et al, 2019) mouse models as well as transgenic rat models (Filipcik et al, 2012) have been developed.…”

“…Tau has been an important target in therapeutics development for AD and primary tauopathies. Immunotherapies semorinemab, gosuranemab ( Boxer et al, 2019 ; Ayalon et al, 2021 ; Grossman, 2021 ; Mullard, 2021 ; Novak et al, 2021 ), antisense oligonucleotides ( DeVos et al, 2017 ), and aggregation inhibitors are at different stages of clinical trials ( Congdon and Sigurdsson, 2018 ). Transgenic animal models recapitulating human tauopathy have enabled understanding of disease mechanisms and facilitated the development of treatment strategies ( Albert et al, 2019 ; Roberts et al, 2020 ; Ayalon et al, 2021 ).…”

“…Immunotherapies semorinemab, gosuranemab ( Boxer et al, 2019 ; Ayalon et al, 2021 ; Grossman, 2021 ; Mullard, 2021 ; Novak et al, 2021 ), antisense oligonucleotides ( DeVos et al, 2017 ), and aggregation inhibitors are at different stages of clinical trials ( Congdon and Sigurdsson, 2018 ). Transgenic animal models recapitulating human tauopathy have enabled understanding of disease mechanisms and facilitated the development of treatment strategies ( Albert et al, 2019 ; Roberts et al, 2020 ; Ayalon et al, 2021 ). Varieties of transgenic mouse lines with mutations on MAPT gene including P301S (PS19), P301L (JNPL3, rTg4510, pR5) ( Lewis et al, 2000 ; Ramsden et al, 2005 ; Santacruz et al, 2005 ; Yoshiyama et al, 2007 ; de Calignon et al, 2012 ), knock-out hTau ( Andorfer et al, 2003 ), and knock-in ( Hashimoto et al, 2019 ; Saito et al, 2019 ) mouse models as well as transgenic rat models ( Filipcik et al, 2012 ) have been developed.…”